Male-Biased Aganglionic Megacolon in the TashT Mouse Line Due to Perturbation of Silencer Elements in a Large Gene Desert of Chromosome 10

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Hirschsprung’s disease (also known as aganglionic megacolon) is a severe congenital defect of the enteric nervous system (ENS) resulting in complete failure to pass stools. It is characterized by the absence of neural ganglia (aganglionosis) in the distal gut due to incomplete colonization of the embryonic intestines by neural crest cells (NCC), the ENS precursors. Hirschsprung’s disease has an incidence of 1 in 5000 newborns and a 4 : 1 male sex bias. Although many genes have been associated with this complex genetic disease, most of its heritability as well as its male sex bias remain unexplained. Here, we describe an insertional mutant mouse line (“TashT”) in which virtually all homozygotes display colonic aganglionosis due to defective migration of enteric NCC, but in which only a subset of homozygotes develops megacolon. Surprisingly, this group is almost exclusively male. The TashT ENS defect stems, at least in part, from the disruption of long-range interactions between evolutionarily conserved elements with silencer activity and Fam162b, resulting in NCC-specific upregulation of this uncharacterized protein coding gene. Global analysis of gene expression further revealed that several hundreds of genes are significantly deregulated in TashT enteric NCC. Interestingly, this dataset includes multiple X-linked candidate genes potentially underlying the male sex bias. Taken together, our data pave the way for a clearer understanding of the intriguing male sex bias of Hirschsprung’s disease.

Vyšlo v časopise: Male-Biased Aganglionic Megacolon in the TashT Mouse Line Due to Perturbation of Silencer Elements in a Large Gene Desert of Chromosome 10. PLoS Genet 11(3): e32767. doi:10.1371/journal.pgen.1005093
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1005093

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